In general, there are some routes for attempting to increase bioavailability of poorly water soluble drugs, amongst which formation of nano-composite particles has attracted interest, and nano-milled suspensions have been utilized (see, e.g., U.S. Pat. No. 7,276,249, which discloses a process of spray coating nano-suspensions onto large carrier particles). The coated fibrate compositions are alleged to have improved pharmacokinetic profiles and reduced fed/fasted variability. There are some related prior-art documents cited in U.S. Pat. No. 7,276,249 dealing with various aspects of production of nano-suspensions and formation of nano-composite powders. However, these references do not demonstrate the forming of films based on nano-suspensions, or more preferably films containing dry nano/micro drug powders, while most of the references require spray coating to produce the final product that may have improved bioavailability due to faster dissolution.
In general, pharmaceutical thin films have attracted attention recently because of their improved patient compliance and the potential for scaling, continuous processing and cost-effective manufacturing. When administered via the buccal route, these thin films rapidly disintegrate in the oral cavity, thereby typically avoiding first pass metabolism and enhancing dissolution and bioavailability of active pharmaceutical ingredients (API).
In general, a desired requirement for incorporating API nanoparticles into thin films is to ensure the drug content uniformity in a film and the stability of its crystalline form. Two commonly used methods for fabrication of pharmaceutical films are hot melt extrusion (HME) and solvent casting technique (SCT). In HME, an API is mixed with a polymer (and excipients) following which both are melted and extruded together through an orifice or die. Broad applications of HME are however limited due to the difficulty in preserving the API in amorphous form and maintaining long term stability. In SCT, polymer-API suspensions or solutions are typically cast on a substrate and dried either via conventional drying techniques (oven drying) or by using a continuous film casting line.
Most of the articles related to SCT address the incorporation of either water soluble APIs or dissolved APIs, where a BCS class II and IV drug compound is dissolved in a suitable non-aqueous solvent. Some of these studies focus on the formulation aspects of films and the impact of processing parameters, and content uniformity are not discussed. U.S. Pat. No. 5,948,430 proposes the use of substantially water soluble low molecular polymers and polyalcohols for forming films intended for quick disintegration and release of active agents. U.S. Pat. Pub. No. 2007/0087036 discloses the preparation of polymer film coated with water soluble nutritional supplement to at least one side of the film layer. The films were prepared separately, and the nutrient mixture in the powder form having an adhesive was coated on the film.
U.S. Pat. No. 7,241,411 discloses the preparation of pullulan and hydroxypropyl cellulose based edible films loaded with water soluble skin care ingredients and other ingredients. U.S. Pat. No. 6,419,903 proposes the use of low molecular weight HPMC along with pre-gelated starch for formation of quick release films with improved texture and patient compliance. U.S. Pat. Pub. No. 2003/0206942 discloses methods for forming buccal films with improved muco-adhesion and longer retention time in the oral cavity. U.S. Pat. No. 7,648,712 discloses the use of AMBERLITE for taste masking active agents such as dextromethorphan. Water soluble polymers including pullulan are used as film formers for buccal delivery. U.S. Pat. No. 6,596,298 discloses methods for forming pullulan films containing antibacterial agents for dental applications. Most of these disclosures adopt conventional drying techniques or coating processes for film formation, and a primary focus is placed on improvement of texture, disintegration and muccoadhesion of films for buccal applications. These disclosures do not discuss the impact of processing parameters or drying methods on final film quality.
In one of the earlier works on SCT, U.S. Pat. No. 4,136,145 disclosed the use of convective drying methods for fabrication of orally dissolving films containing an active agent. However, in a later study conducted by Schmidt (U.S. Pat. No. 4,849,246) it was reported that the processing regimes suggested by U.S. Pat. No. 4,136,145 resulted in non-uniform films. These drawbacks were attributed to long drying times associated with the processing conditions suggested by the '145 patent.
U.S. Pat. No. 5,629,003 discusses the importance of film precursor viscosity on final uniformity of film, and proposes the use of film modifiers or viscosity enhancing agents in the film formulation. This method also proposes the use of a film coating unit for drying of the films. U.S. Pat. No. 7,824,588 discloses the preparation of pullulan and hydroxypropyl cellulose based edible films loaded with water insoluble pharmaceutical active ingredients. Films having different thicknesses loaded with active ingredients were prepared at different drying conditions. The uniformity of active ingredient in the films was measured by weight measurements of cut films, and with UV absorption studies. U.S. Patent Pub. No. 2008/0075825 discloses the use of flavoring agents like orange flavor, mint flavor, etc., as de-foaming agents.
The use of de-foaming agents could lead to inhomogeneous film as these agents impact the spreading of suspensions onto the substrate. This disclosure discusses in detail, various problems associated with air entrapment in films. However, the drying techniques discussed in the disclosures of U.S. Pat. No. 7,824,588, U.S. Patent Pub. 2008/0075825 and U.S. Pat. No. 5,629,003 are applied to melted suspensions obtained through HME techniques. As mentioned previously, this method leads to amorphous APIs, which tend to re-crystallize. Thus, maintaining the long-term stability of these dosages remains a challenge. Moreover, these drying methods use high temperatures (beyond the melting point of the API) and harsh drying conditions, which cannot be applied for SCT or even in cases where the API is protein based (like insulin) or heat sensitive.
The prior art does not discuss the incorporation and stabilization of nano and/or micro BCS class II API particles in strip films. As can be inferred from the discussions above, there are some challenges associated with strip film technology, e.g., maintenance of API content uniformity and retaining the API structure or form. Yang (U.S. Pat. No. 7,824,588) discusses the various factors that could affect the final content uniformity of the film: formation of air pockets during mixing, improper casting, viscosity of the starting precursor solutions, improper drying methods (associated with long drying times), final water content of films, etc. These challenges escalate when API is to be incorporated in nano or micro form.
These particles can aggregate or grow if the film processing conditions are not favorable. U.S. Pat. Pub. No. 2011/0305768 discloses the preparation of quick dissolving films containing pH-sensitive micro particles encapsulated with bioactive agents. The pH-sensitive micro particles were prepared by a double emulsion solvent evaporation method. Though this method offers targeted release of protein-based compounds, it is a complicated and time-consuming process. Further, this method is not cost effective, and the final product may contain residual organic solvents. Researchers have discussed the incorporation and stabilization of micro griseofulvin (GF) particles produced via a liquid anti-solvent precipitation (LASP) method into HPMC strip films, which also suffers from the potential problem of residual organic solvents.
Thus, an interest exists for improved systems and methods for improved stripfilm based pharmaceutical products. These and other inefficiencies and opportunities for improvement are addressed and/or overcome by the systems, assemblies and methods of the present disclosure.